Drug resistance evolves in inbred parasites

It all starts with a mosquito bite. When a hungry mosquito pierces someone’s skin to gorge herself, she also pumps in her saliva to stop the blood from clotting. Far too often, microscopic stowaways hiding in the insect’s salivary glands also make the trip, crossing over into the victim’s bloodstream to look for a new home. These serpentine parasites swim along the blood vessels, making their way to the liver and infecting liver cells within just a few minutes. They hide inside these cells for anywhere from a week to a month (or even several months, in some cases), copying their DNA and growing larger and larger as they prepare for the next stage of their life. Eventually, the growing mass breaks up. A swarm of single-celled parasites bursts out of the liver cells and into the blood; once there, they invade red blood cells, feeding on their haemoglobin and energy stores to fuel another reproductive burst which will infect more red blood cells. As the parasite spreads through the blood, the unfortunate host will start showing the symptoms of malaria — everything from headaches and joint pain to fever, vomiting, and even convulsions. When a mosquito bites an infected person, she sucks up the parasite as part of her bloody meal. The malaria parasite mates within the mosquito, going through several stages before producing the serpentine cells that migrate to the salivary glands, ready to start the entire cycle anew.

Malaria takes the life of an African child every minute. A report by the World Health Organization (WHO) in 2010 estimated that over 200 million people had malaria, with the highest rates in sub-Saharan Africa and South-East Asia. Despite extensive research, we still don’t have a vaccine against malaria; for now, prevention efforts mainly consist of controlling mosquito populations and sleeping under insecticide-treated mosquito nets. Fortunately, several anti-malarial drugs are available, though the fast-evolving parasite has a knack for becoming resistant to these treatments.

The most effective drugs available are based on derivatives of artemisinin, an ancient Chinese remedy extracted from sweet wormwood. Artemisinin derivatives became the malaria treatment of choice in the 1990s; in 2006, the WHO issued guidelines recommending that they only be used as part of a mixed cocktail of drugs to slow the emergence of resistance. Despite these efforts, artemisinin resistant populations of the malaria parasite have appeared in western Cambodia and the neighbouring regions in recent years. This is especially worrying because resistance to other anti-malarial drugs also showed up in western Cambodia first before spreading to the rest of the world.

To understand how and why artemisinin resistance evolved in western Cambodia, an international team of scientists sequenced the genomes of over 800 malaria parasites from populations in West Africa and South-East Asia. By comparing the genomes, the researchers identified different sub-populations of the parasite and traced how they were related to each other. To their surprise, they found that the samples from western Cambodia stood out not only from the African populations, but also from other South-East Asian samples. Looking more closely, they discovered three strikingly different sub-populations of resistant parasites in western Cambodia. “It’s as if there are different ethnic groups of artemisinin-resistant parasites inhabiting the same region,” said Professor Dominic Kwiatkowski, senior author of the study, in a press release. Based on how distinct they are and other evidence from their genomes, the researchers concluded that each sub-population recently expanded from a small initial group.

But why do these resistant populations all show up in western Cambodia? The researchers think it’s because resistance results from the joint effect of many small genetic changes. Since the parasite populations in western Cambodia are highly inbred, it’s more likely that the right changes will all come together in a single individual. If that idea is correct, you would expect to find distinct, highly inbred populations of resistant parasites descended from small founder groups, which is just what the team saw.

This work has an immediate and tangible public health impact. The genetic differences discovered by the team can be used as molecular markers to identify and track artemisinin resistant strains. “Our approach allows us to identify emerging populations of artemisinin-resistant parasites, and monitor their spread and evolution in real time,” said Dr Olivo Miotto, one of the authors, in a press release. “This knowledge will play a key role in informing strategic health planning and malaria elimination efforts.” The study also uncovered changes in several genes which might be responsible for artemisinin resistance. We can only hope that these leads will help scientists discover ways to overcome resistant strains and prevent needless deaths from this unrelenting disease.